The objective of this program is to test the hypothesis that 5- HT1B receptors play an important modulatory role in the reinforcing effects of ethanol. The reasons for undertaking this research are compelling; in particular, 1. 5-HT1B receptors appear to be an important part of the brain circuitry involved in reinforcement - they are distributed in a highly localized fashion in the mammalian brain, with notable concentrations in critical reward-relevant regions including the ventral tegmental area, dorsal raphe and amygdala, and; 2. contemporary research has begun to implicate these receptors in drug dependence processes. However, this latter evidence is preliminary with respect to ethanol reinforcement, due primarily to the limited availability of selective receptor agonists and antagonists. Our research will use more selective agonists and antagonists to assess a) their acute and chronic effects on ethanol motivated responding in an operant paradigm to confirm that 5-HT1B manipulations do indeed modify ethanol self-administration, b) the impact of regional manipulations of 5-HT1B receptor function following focal administration of selective agents in order to elucidate the importance of specific CNS regions in regulating ethanol self-administration, and c) determine the relative contribution played by dopaminergic and glutamatergic projections, from the ventral tegmental area and amygdala respectively, in mediating the effects of 5-HT1B receptor manipulations in these regions. This will elucidate other neural substrates involved in modifying ethanol self-administration and the interplay between them. Control experiments are designed to confirm that these effects are not due to alterations in ethanol kinetics, taste effects or caloric variables. These comprehensive studies will provide important new information on the role of 5-HT1B receptors in controlling EtOH self-administration. While humans do not express 5-HT1B receptors there is tremendous similarity between the rat 5-HT1B and human 5-HT1Dbeta receptor subtypes. Specifically, they show an overall amino acid identity of 93 percent, as well as displaying similar pharmacology, second messenger coupling and anatomical distributions. Therefore, animal studies investigating the functional role of this receptor subtype do have relevance to further our understanding of the important role of central 5-HT1Dbeta receptors in humans. A central role of 5-HTergic systems in ethanol reinforcement has been recognized for some time; this research will provide new knowledge about highly selective serotonergic manipulations which may well lead to future treatment applications.